PDF(Pubmed)
Abstract：
BACKGROUND: This study explores the potential role of Thioredoxin-interacting protein (TXNIP) silencing in endothelial colony-forming cells (ECFCs) within the scope of age-related comorbidities and impaired vascular repair. We aim to elucidate the effects of TXNIP silencing on vasculogenic properties, paracrine secretion, and neutrophil recruitment under conditions of metabolic stress.
METHODS: ECFCs, isolated from human blood cord, were transfected with TXNIP siRNA and exposed to a high glucose and β-hydroxybutyrate (BHB) medium to simulate metabolic stress. We evaluated the effects of TXNIP silencing on ECFCs\' functional and secretory responses under these conditions. Assessments included analyses of gene and protein expression profiles, vasculogenic properties, cytokine secretion and neutrophil recruitment both in vitro and in vivo. The in vivo effects were examined using a murine model of hindlimb ischemia to observe the physiological relevance of TXNIP modulation under metabolic disorders.
RESULTS: TXNIP silencing did not mitigate the adverse effects on cell recruitment, vasculogenic properties, or senescence induced by metabolic stress in ECFCs. However, it significantly reduced IL-8 secretion and consequent neutrophil recruitment under these conditions. In a mouse model of hindlimb ischemia, endothelial deletion of TXNIP reduced MIP-2 secretion and prevented increased neutrophil recruitment induced by age-related comorbidities.
CONCLUSIONS: Our findings suggest that targeting TXNIP in ECFCs may alleviate ischemic complications exacerbated by metabolic stress, offering potential clinical benefits for patients suffering from age-related comorbidities.
METHODS: ECFCs, isolated from human blood cord, were transfected with TXNIP siRNA and exposed to a high glucose and β-hydroxybutyrate (BHB) medium to simulate metabolic stress. We evaluated the effects of TXNIP silencing on ECFCs\' functional and secretory responses under these conditions. Assessments included analyses of gene and protein expression profiles, vasculogenic properties, cytokine secretion and neutrophil recruitment both in vitro and in vivo. The in vivo effects were examined using a murine model of hindlimb ischemia to observe the physiological relevance of TXNIP modulation under metabolic disorders.
RESULTS: TXNIP silencing did not mitigate the adverse effects on cell recruitment, vasculogenic properties, or senescence induced by metabolic stress in ECFCs. However, it significantly reduced IL-8 secretion and consequent neutrophil recruitment under these conditions. In a mouse model of hindlimb ischemia, endothelial deletion of TXNIP reduced MIP-2 secretion and prevented increased neutrophil recruitment induced by age-related comorbidities.
CONCLUSIONS: Our findings suggest that targeting TXNIP in ECFCs may alleviate ischemic complications exacerbated by metabolic stress, offering potential clinical benefits for patients suffering from age-related comorbidities.
摘要：
背景：这项研究探讨了硫氧还蛋白相互作用蛋白（TXNIP）沉默在内皮集落形成细胞（ECFCs）中的潜在作用，在与年龄相关的合并症和血管修复受损的范围内。我们旨在阐明TXNIP沉默对血管生成特性的影响，旁分泌,代谢应激条件下的中性粒细胞募集。
方法：ECFC，从人的脐带血中分离出来，用TXNIPsiRNA转染并暴露于高葡萄糖和β-羟基丁酸(BHB)培养基以模拟代谢应激。我们评估了在这些条件下TXNIP沉默对ECFCs功能和分泌反应的影响。评估包括基因和蛋白质表达谱的分析，血管生成特性，体外和体内细胞因子分泌和中性粒细胞募集。使用后肢缺血的鼠模型检查体内作用，以观察TXNIP调节在代谢紊乱下的生理相关性。
结果：TXNIP沉默并未减轻对细胞募集的不利影响，血管生成特性，或ECFC中代谢应激诱导的衰老。然而,在这些条件下，它显着降低了IL-8的分泌和随后的中性粒细胞募集。在后肢缺血的小鼠模型中，TXNIP的内皮缺失减少了MIP-2的分泌,并阻止了年龄相关合并症引起的中性粒细胞募集增加.
结论：我们的研究结果表明，在ECFCs中靶向TXNIP可以减轻代谢应激加剧的缺血性并发症，为患有年龄相关合并症的患者提供潜在的临床益处。
方法：ECFC，从人的脐带血中分离出来，用TXNIPsiRNA转染并暴露于高葡萄糖和β-羟基丁酸(BHB)培养基以模拟代谢应激。我们评估了在这些条件下TXNIP沉默对ECFCs功能和分泌反应的影响。评估包括基因和蛋白质表达谱的分析，血管生成特性，体外和体内细胞因子分泌和中性粒细胞募集。使用后肢缺血的鼠模型检查体内作用，以观察TXNIP调节在代谢紊乱下的生理相关性。
结果：TXNIP沉默并未减轻对细胞募集的不利影响，血管生成特性，或ECFC中代谢应激诱导的衰老。然而,在这些条件下，它显着降低了IL-8的分泌和随后的中性粒细胞募集。在后肢缺血的小鼠模型中，TXNIP的内皮缺失减少了MIP-2的分泌,并阻止了年龄相关合并症引起的中性粒细胞募集增加.
结论：我们的研究结果表明，在ECFCs中靶向TXNIP可以减轻代谢应激加剧的缺血性并发症，为患有年龄相关合并症的患者提供潜在的临床益处。
